Pharmacogenetic Optimization of Analgesic Prescribing in Sickle Cell Disease

镰状细胞病镇痛处方的药物遗传学优化

• 批准号: 8190974
• 负责人: Cheedy Jaja
• 金额: $ 9.4万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8190974
• 关键词: Absence of pain sensation; Accident and Emergency department; Acute; Acute Pain; Address; Adverse event; Advisory Committees; Algorithms; Analgesics; Biological Markers; CYP2C19 gene; CYP2C9 gene; CYP2D6 gene; Caring; Cessation of life; Clinical; Cohort Studies; Couples; Cytochrome P450; Cytochromes; Data; Development; Dose; Drug Monitoring; Drug Tolerance; Enzymes; Exposure to; Failure; Foundations; Functional disorder; Funding; Genes; Genetic; Genetic Polymorphism; Genotype; Goals; Growth and Development function; Incidence; Individual; Inherited; Intervention; Laboratories; Link; Mentored Research Scientist Development Award; Mentors; Metabolic; Mission; Modeling; Monitor; Mutation; National Institute of Nursing Research; Observational Study; Opioid; Opioid Analgesics; Outcome; Pain; Pain Disorder; Pain management; Patients; Pharmaceutical Preparations; Pharmacogenetics; Pharmacotherapy; Phenotype; Play; Prevalence; Principal Investigator; Publishing; Regimen; Research; Research Personnel; Research Support; Research Training; Resources; Risk; Risk Estimate; Risk Factors; Role; Scientist; Sickle Cell Anemia; Susceptibility Gene; Techniques; Testing; Therapeutic; Training; Training Programs; Translational Research; Variant; Visit; adverse outcome; authority; base; career; chronic pain; clinical practice; design; dosage; drug metabolism; experience; high risk; medical schools; mortality; programs; prospective; response; therapy design

DESCRIPTION (provided by applicant): This proposal describes a three year mentored training program for Dr. Cheedy Jaja to create a robust foundation in sickle cell disease (SCD) pharmacotherapy and analgesic pharmacogenetics essential for his transition to an independent translational research scientist with expertise in SCD pain management. A customized program of study that couples didactic coursework and research training with clinical and laboratory training in SCD pathophysiology, pain management and pharmacogenetics is designed. Dr. Abdullah Kutlar, a leading authority in SCD pain management will mentor the principal investigator's scientific growth and development, and an advisory committee of highly regarded SCD researchers and translational scientists will provide scientific and research support. The proposed mentored training draws on the excellent SCD research and clinical resources available at the Medical College of Georgia and encompasses a prospective cohort study. This study seeks to shift clinical practice by challenging the current "as-needed" opioids strategy. Although it is known to exist, the exact incidence and prevalence of suboptimal analgesic prescribing practices in SCD patients is unknown. The absence of this information is a critical barrier to progress in optimizing analgesic therapy. This proposed study approach to addressing this critical barrier is to focus on genetic polymorphisms in cytochrome P450 genes which are known to play a role in analgesic drug metabolism and could help identify patients with higher risk for therapy failure. The study is designed to test the central hypothesis that deficient cytochrome CYP2C9, CYP2C19 and CYP2D6 metabolic phenotypes and suboptimal analgesic prescribing are positively associated with ED visits in SCD patients; and to demonstrate that CYP450 phenotypes information can be used for estimating risks for repeated ED visits for analgesic therapy failure. The Tag-It Mutation Technique is used to determine CYP450 genotypes, and the Medication Quantification Scale is used to determine suboptimal prescribing incidence. The central hypothesis if confirmed, will establish deficient CYP450 phenotypes and exposure to suboptimal prescribing as clinical risk factors. The study risk prediction rules will guide clinicians in identifying individuals who would benefit from targeted, individualized intervention to reduce risks for repeated ED visits. The study will transform current clinical practice deconstructively by demonstrating that suboptimal prescribing is common in SCD analgesic therapy. Constructively, the study will establish feasibility of CYP450 phenotyping for identifying patients likely to achieve successful analgesic relief from conventional analgesic dosing regimens or patients who might benefit from analgesic switching. PUBLIC HEALTH RELEVANCE: This project addresses pain and its management with opioid analgesics in patients with sickle cell disease. By linking suboptimal prescribing of analgesics and deficiency in inherited metabolic capacity in SCD patients to frequent utilization of acute care resources, we may identify possible risk factors for poor pharmacotherapeutic outcomes in SCD patients and validate the need for genotyping to identify at-risk SCD patients for analgesic drugs failure.

描述（由申请人提供）：该提案描述了Cheedy Jaja博士为期三年的指导培训计划，以在镰状细胞病（SCD）药物疗法和镇痛药遗传学方面创建坚固的基础，这对于他过渡到具有SCD疼痛管理专业知识的独立翻译研究科学家至关重要。一项定制的研究计划，设计了伴侣的教学课程和研究培训，并设计了SCD病理生理学，疼痛管理和药物遗传学方面的临床和实验室培训。 SCD疼痛管理领先的领先权威Abdullah Kutlar博士将指导首席研究者的科学成长和发展，并且由备受推崇的SCD研究人员和转化科学家组成的咨询委员会将提供科学和研究支持。拟议的指导培训借鉴了佐治亚医学院提供的出色SCD研究和临床资源，并涵盖了一项前瞻性队列研究。这项研究试图通过挑战当前的“需要”阿片类药物策略来改变临床实践。尽管已知存在，但SCD患者中次级镇痛药的确切发生率和流行率尚不清楚。缺乏这些信息是优化镇痛疗法进展的关键障碍。解决这一关键障碍的这种研究方法是关注细胞色素P450基因的遗传多态性，该基因已知在镇痛药物代谢中发挥作用，并可以帮助识别患有较高治疗衰竭风险的患者。该研究旨在检验中心假设，即缺乏细胞色素CYP2C9，CYP2C19和CYP2D6代谢表型以及次优镇痛药的处方与SCD患者的ED访问正相关；并证明CYP450表型信息可用于估计镇痛治疗衰竭反复访问的风险。标签-IT突变技术用于确定CYP450基因型，药物定量量表用于确定次优处方的发生率。中央假设如果确认，将建立不足的CYP450表型，并将其作为临床风险因素的次优处方。研究风险预测规则将指导临床医生确定将从有针对性的个性化干预措施中受益的个人，以降低反复访问的风险。该研究将通过证明次优处方在SCD镇痛疗法中常见，从而改变当前的临床实践。这项研究将建立CYP450表型的可行性，以识别可能从常规的镇痛剂量治疗方案或可能从镇痛性转换中受益的患者成功缓解镇痛药。 公共卫生相关性：该项目解决了镰状细胞疾病患者的阿片类镇痛药的疼痛及其管理。通过将SCD患者的镇痛药的次级处方和遗传代谢能力的不足联系起来，以频繁利用急性护理资源，我们可能会确定SCD患者药物治疗不良结果的可能风险因素，并鉴定出基因分型的需求，以便基因分型以使处于高危SCD患者的仿制药物失效。